Method of producing (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide

专利摘要:
The invention relates to substituted pyrrolidine, in particular the preparation of (S) -ot.-3Tmi-2-oKco-1-pyrrodinacetamide, which has antihypoxic and anti-ischemic activity and can be used in medicine. The purpose of the invention is to create an active and low-toxic substance of the indicated class. Synthesis of lead cyclization
公开号:SU1428195A3
申请号:SU864027938
申请日:1986-08-13
公开日:1988-09-30
发明作者:Гобэр Жан；Жерт Жан-Пьер；Бодзон Ги
申请人:Юцб С.А. (Фирма)；
IPC主号:

专利说明:

The invention relates to the preparation of a novel compound - (5) -alpha-ethyl-2-OXO-1-pyrrolidine acetamide, which has antihypoxic and anti-ischemic activity.
The purpose of the invention is to develop, on the basis of known methods, a method of obtaining a new compound that possesses valuable pharmacological properties with low toxicity.
Example 1. a) Obtaining ethyl- (8) -4 - // 1- (aminocarbonyl) propyl / - / -amino / butyrate.
To a suspension of 47.75 g (0.345 mol) of (8) -2-aminobutanamide hydrochloride (alpha: + 26.1 °; methanol), 143.6 ml (1.035 mol) of triethylamine are added to 400 ml of toluene. The mixture is heated before and 67.2 g (0.345 mol) of ethyl 4-bromobutyrate are added dropwise to it.
The reaction medium is maintained at 80 ° C for 10 hours, then filtered while hot to remove triethylamine salts. The filtrate is evaporated under reduced pressure to obtain 59 g of an oily residue, consisting mainly of the monoalkylation product and containing a small amount of the dialkyl derivative.
The crude product obtained was used as such without further purification to obtain (S) - alpha-ethyl-2-oxo-1-pyrrolidineacetamide by cyclization,
b) Preparation of (5) -alpha-ethyl-2-oxo-1-pyrrolidine acetamide.
54 g of the crude product obtained in a) are dissolved in 125 ml of toluene in the presence of 2 g of 2-hydroxypyridine. Maintain the mixture at 110 ° C for 12 hours.
The insoluble material is filtered off in the hot state. Then the filtrate is evaporated under reduced pressure. The residue is purified by chromatography on a column of 1.1 kg of silica (column diameter 5 cm; eluent is a mixture of ethyl acetate, methanol and concentrated ammonia in a volume ratio of 85: 12: 3),
The isolated product is recrystallized from 50 ml of ethyl acetate. Thus, 17.5 g of (3) -alpha-ethyl-2-oxy-1-pyrrolidine acetamide, T, mp, 117 ° C alpha: -90.0 ° (, acetone) are obtained. Yield 41%
ten
15
20
25
thirty
35
40
45
50
55
Example 2, a) Preparation of (S) -N- / 1- (aminocarbonyl) propyl / -4-chlorobutane.
345.6 g (2.5 mol) of crushed potassium carbonate and 138.5 g (1 mol) of (8) -2-amino-butanamide hydrochloride are mixed in 2.5 l of acetonitrile. The reaction mixture is cooled to a temperature of approximately 0 ° C and a solution of 129.2 g (1.2 mol) of 4-chlorobutyryl chloride in 500 ml of acetonitrile is dropped into it. After the addition is complete, the reaction mixture is allowed to warm to ambient temperature. The insoluble matter is separated by filtration and the filtrate is introduced into the filtrate under reduced pressure. The resulting crude residue is stirred for 30 minutes in 1.2 liters of anhydrous ether at 5-10 ° C, the precipitate is filtered off, washed with it twice. 225 ml of ether and dried in vacuo. Thus, 162.7 g (S) - H- / 1-Saminocarbonyl) propyl / 4-chlorobutanamide are obtained, T, mp, 118-123 s, alpha j, -18 ° (, methanol). The output of 78.7%,
The crude product thus obtained is quite suitable for the next cyclization step. However, it can be purified by stirring for 1 hour in anhydrous ethyl acetate, T, mp, 120-122 ° C, alpha: -22.2 ° (, methanol),
b). Preparation of (5) -alpha-ethyl-2-ox-1-pyrrolidine acetamide,
Under a nitrogen atmosphere, 45 g (0.03 mol) of (S) -N- (1- (aminocarbonyl) propyl) -4-chlorobutanamide and 0.484 g (0.0015 mol) of tetrabutylammonium bromide are mixed in 45 ml of dichloromethane. A. Within 30 minutes, the temperature of the reaction mixture is not exceeding + 2 ° C, 2.02 g (O, 036 mol) of powdered potassium hydroxide. Then the mixture is stirred for 1 h. To this is added another 0.1 g. (0.0018 mol) of crushed potassium hydroxide and stirred for another 30 minutes at 0 ° C. Allow to warm to ambient temperature. I Remove the insoluble matter by filtration and concentrate comfort filtrate under reduced pressure, ny The resulting residue was recrystallized in 40 ml of ethyl acetate in the presence of 1.9 g molecular sieve 0.4 nm, which ud, l eatem removed by filtration in the hot state. obra3 thereby obtained,
Zones of 3.10 g (5) -alpha-ethyl-2-oxo-1-pyrrolidine acetamide. T. pl. 116.7 C, alpha: -90.1 ° (, acetone). Yield 60.7%.
Example 3. Preparation of (8) -alpha-ethyl-2-oxo-1-pyrrolidine acetamide
This example illustrates a variation of the method of Example 2, according to which the intermediate 4-chlorobutanamide, prepared in situ, is not isolated.
To a suspension of 69.25 g (0.5 mol) of (3) -2-aminobutanamide hydrochloride in 600 ml of dichloromethane, 84 g of anhydrous sodium sulfate is added at ambient temperature. Cool to 0 ° C and add 115 g of powdered potassium hydroxide, then 8.1 g (0.025 mol) of tetrabutylammonium bromide dissolved in 100 ml of dichloromethane. With vigorous stirring, a solution of 77.5 g of 4-chlorobutyl chloride in 100 ml of dichloromethane is added dropwise at OC. After 5 hours of reaction, another 29 g of powdered potassium hydroxide is added. After 2 h, the reaction mixture was filtered through byflo-cel and the filtrate was evaporated under reduced pressure. The residue (93.5 g) is dispersed in 130 ml of hot toluene for 45 minutes. Filter and extrude under reduced pressure. The residue (71.3 g) is dissolved in a hot state in 380 ml of ethyl acetate, to which 23 g of molecular sieve 0.4 nm is added as a powder. This mixture is heated with reflux and filtered while hot. After cooling the filtrate, the desired product crystallizes. 63 g of (S) -alpha-etch1-2-oxo-1-pyrrolidine acetamide are thus obtained. T. pl. 117 C. alpha: -91.3 ° (, acetone). The yield is 74.1%.
Pharmaceutical tests.
Racemic alpha-ethyl-2-oxo-1-pyrrolidine acetamide (product A) and (S) - alpha ethyl-2-oxo-pyrrolidine acetamide (product B) prepared according to the invention were subjected to pharmacological tests.
1. Protection against hypoxia (mice).
The principle of this test is to measure the survival of an organism exposed to the atmosphere progressively depleted of oxygen. Taking into account the special sensitivity of the nervous system to this type of damage, the results obtained
with
Q
n 5,.
0
0
five
95
This test can be interpreted as a measure of the resistance of the nervous system. Therefore, products that increase the resistance of animals are suitable for the treatment and prevention of aggression of the central nervous system of a hypoxic nature.
The technique. The device is a sealed transparent cell 37 cm high, 39 cm deep and 97 cm wide. This 140-liter cell has 60 transparent compartments 6 10 10 in size (10 cm), which can be insulated with 60 cubic meters.
The fan provides mixing of the atmosphere circulating in the compartments through the grid floor. The cell is equipped with a nitrogen inlet device with a constant flow rate and an opening in communication with ambient air. .
male animals (CNMRI) weighing 20-22 g are taken as animals. They are no longer given food on the eve of the trial. The experiment was carried out the following day simultaneously with three groups of 20 mice; the control group receives orally water (25 ml / kg), and the remaining two groups receive each test product orally.
25 minutes after administration, the animals are redistributed at random between the compartments in such a way that none of the three groups fall into the best C7 in the cell.
30 minutes after the introduction of the cage (
The furnace is closed and nitrogen is introduced at a constant flow rate (7.750 liters of technical nitrogen per minute) for approximately 37 minutes. By this time, the atmosphere contains 3.7% oxygen. The cage is left closed until a critical time — when out of twenty control animals, not more than three survive. At this time, the cell is opened and the surrounding air is admitted into it. After a few moments, the under-: read the number of surviving animals in each group.
The experiments are repeated for each dose of the test product once or twice. The results are summarized to obtain a minimum of 40 (or 60) animals per dose and 40 (60) corresponding control animals.
For each dose of product tested, the number of surviving animals
among those treated with this product are compared with the number of surviving control animals. The difference between these numbers expresses the protective activity of the product in relation to hypoxia caused by lack of oxygen. The statistical value {YT of this difference is assessed by Fischer-Gates test.
Table 1 shows the results obtained for increasing doses of products A and B, (
Table 1
Note, -NS- difference is negligible
In this experiment, a levorotatory enantiomer obtained according to the invention (product B) increases the survival of animals lacking oxygen, starting with a dose of 0.032 mmol / kg. The racemate (product A) shows a similar activity only starting with a dose of 0.32 mmol / kg (the first effective dose), and therefore, it is 10 times less active than the left-handed enantiomer,
2. Protection against cerebral ischemia (rats).
Principle. Electroencephalographic examinations show that transferring two common carotid arteries in rats causes true cerebral ischemia: the curve of the electroencephalogram becomes flat and even isoelectric (electrical pause).
The technique. Male Wistar rats weighing 250-350 g are anesthetized with pentobarbitol, which is administered intraperitoneally at a dose of 50 mg / kg (0.5 ml / 100 g).
Immediately after anesthesia, the animals are administered intraperitoneally, at the rate of
0.5 ml / 100 g, either the test product dissolved in isotonic sodium chloride solution (treated animals), or only isotonic sodium chloride solution, or placebo (control animals,
Approximately 20 minutes later, a ligature is removed from both common carotid arteries and after about 10 minutes they are ligated simultaneously. This operation is performed simultaneously on the control and treated animals.
One hour after the administration of the test -. The product or placebo is administered intraperitoneally again the same dose of either the test product (treated animals) or placebo (control animals).
Five hours after the first administration, the dose of either the test product (surviving treated animals) or placebo (surviving control animals) is administered for the third time.
24 hours after the first administration, all animals are examined under anesthesia.
Zia, caused by pentobarbitol, the effectiveness of the ligature by cutting the carotid arteries below the ligature. The number of surviving animals is noted from both treated and control animals. For a catch of the dose of the product tested, the number of surviving animals from the products treated with this product is compared with the number of surviving animals from the controls. The difference stimulates the protective activity of the product against lethality caused by simultaneous ligature of both carotid arteries. The statistical value (P) of this difference is assessed by the Brandt-Snedecor test,
Table 2 shows the results obtained for increasing doses of products A and B.
Table 2
Note. NS difference is insignificant
From table 2 it follows that the racemate (product A) is active only starting from a dose of 0.64 mmol / kg. In contrast, the left-handed enantiomer obtained according to the invention (product B),
protects animals from death caused by the simultaneous ligature of both carotid arteries, starting with a dose of 0.16 mmol / kg, therefore, it is four times more active than the racemate.
Toxicity. Table 3 lists, for products A and B, the LD mg / kg values, when administered intravenously, determined in male mice, to male rats.
Table3
1790
1500
20
1081
1038
From Table 3 it follows that the levorotating enantiomer obtained according to the invention (product B) is, like the racemate (product A), very low toxic, and that the toxic dose is much more than the active dose.

权利要求:
Claims (1)
[1]
Claims.
The method of obtaining (8) -alpha-ethyl-2-oxo-1-pyrrolidine-acetamide, about t is similar in that (S) -2-aminobutanamide of the general formula
X-CH2-CH-Y-gass (CrH5) CO2, where X is ZOOC with Y -CH "-, where Z is C-C-alkyl,
or X is HalCH, with Y —CO—, where Hal is halogen,
cyclized in an inert organic solvent in the presence of 2-hydroxypyridine or tetrabutylammonium bromide as a catalyst, respectively.

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

EA002380B1|1999-07-21|2002-04-25|Российский Государственный Педагогический Университет Им. А.И.Герцена|Anti-ischimic preparation|GB1309692A|1970-02-13|1973-03-14|Ucb Sa|N-substituted lactams|

---

GB1583871A|1976-10-19|1981-02-04|Ucb Sa|Anti-aggregants|

---

FR2418790B1|1978-03-02|1981-01-09|Rhone Poulenc Agrochimie|

---

GB8412358D0|1984-05-15|1984-06-20|Ucb Sa|Pharmaceutical composition|GB8827389D0|1988-11-23|1988-12-29|Ucb Sa|Process for preparation ofalpha-ethyl-2-oxo-1-pyrrolidineacetamide|

---

IT1231477B|1989-07-12|1991-12-07|Sigma Tau Ind Farmaceuti| ACETAMIDES AS ACTIVATORS OF LEARNING PROCESSES AND MEMORY AND PHARMACEUTICAL COMPOSITIONS INCLUDING SUCH COMPOUNDS|

---

GB9319732D0|1993-09-24|1993-11-10|Ucb Sa|Use of -alpha-ethyl-2-oxo-l-pyrrolidineacetamide for the treatment of anxiety|

---

US6107492A|1998-05-08|2000-08-22|Ucb, S.A.|Process for the preparation of levetiracetam|

---

US6124473A|1998-05-08|2000-09-26|Ucb, S.A.|Process for preparing - and -α-ethyl-2-oxo-1-pyrrolidineacetamide|

---

EA002379B1|1999-07-21|2002-04-25|Российский Государственный Педагогический Университет Им. А.И.Герцена|Remedy having anti-ischemic, antihypoxic and hypotensive activities|

---

KR20030016205A|1999-12-01|2003-02-26|유씨비 소시에떼아노님|A pyrrolidineacetamide derivative alone or in combination for treatment of cns disorders|

---

GB0004297D0|2000-02-23|2000-04-12|Ucb Sa|2-oxo-1 pyrrolidine derivatives process for preparing them and their uses|

---

US6686477B2|2000-09-29|2004-02-03|Eastman Chemical Company|Highly enantiomerically pure lactam-substituted propanoic acid derivatives and methods of making and using same|

---

EP1339669B1|2000-11-21|2008-06-04|UCB Pharma, S.A.|N-alkylated gaba compounds, processes for their preparation and their use as medicaments|

---

WO2002053153A1|2000-12-28|2002-07-11|Daiichi Pharmaceutical Co., Ltd.|Medicines for treatment and prevention of neurogenic pain|

---

US20040116505A1|2001-02-23|2004-06-17|Gregory Krauss|Treatment of tics, tremors and related disorders|

---

US7122682B2|2001-08-10|2006-10-17|Ucb, S.A.|Oxopyrrolidine compounds, preparation of said compounds and their use in the manufacturing of levetiracetam and analogues|

---

HU0401667A2|2001-10-08|2004-12-28|Ucb, S.A.|Use of 2-oxo-1-pyrrolidine derivatives for the preparation of a drug for treatment of dyskinesia and movement disorders|

---

AU2003242538A1|2002-05-14|2003-11-11|Ucb, S.A.|Use of 2-oxo-1-pyrrolidone derivatives for the preparation of a drug|

---

CA2515090A1|2003-02-03|2004-08-19|Teva Pharmaceutical Industries Ltd|Process for producing levetiracetam|

---

ES2214147B1|2003-02-28|2005-10-01|Farma-Lepori S.A.|PROCEDURE FOR OBTAINING AN ANTIEPILEPTIC AGENT.|

---

US20050143445A1|2003-03-18|2005-06-30|Parthasaradhi Reddy B.|Novel crystalline forms of levetiracetam|

---

EP1663968A1|2003-09-05|2006-06-07|Ranbaxy Laboratories Limited|Process for the preparation of pure levetiracetam|

---

ES2390455T3|2003-09-24|2012-11-13|Ucb Pharma, S.A.|Procedure for the preparation of 2-oxo-1-pyrrolidine derivatives|

---

CN1906160A|2003-12-02|2007-01-31|Ucb股份有限公司|Imidazole derivatives, processes for preparing them and their uses|

---

CA2497062A1|2004-02-18|2005-08-18|Dr. Reddy's Laboratories Limited|Preparation of amino acid amides|

---

CA2488325C|2004-11-22|2010-08-24|Apotex Pharmachem Inc.|Improved process for the preparation of -alpha-ethyl-2-oxo-1-pyrrolidineacetamide and -alpha-ethyl-2-oxo-1-pyrrolidineacetamide|

---

MX2007009088A|2005-01-27|2007-09-13|Alembic Ltd|Extended release formulation of levetiracetam.|

---

WO2006088864A1|2005-02-16|2006-08-24|Elan Pharma International Limited|Controlled release compositions comprising levetiracetam|

---

US20070298098A1|2005-02-16|2007-12-27|Elan Pharma International Limited|Controlled Release Compositions Comprising Levetiracetam|

---

WO2006090265A2|2005-02-28|2006-08-31|Ranbaxy Laboratories Limited|Processes for the preparation of levetiracetam, its intermediate and the use of levetiracetam in pharmaceutical compositions|

---

EP1863761A1|2005-03-10|2007-12-12|Rubamin Limited|Process for preparing levetiracetam|

---

US8216611B2|2005-03-30|2012-07-10|Mylan Pharmaceuticals Ulc|Combined-step process for pharmaceutical compositions|

---

US20080194840A1|2005-04-01|2008-08-14|Rubamin Laboratories Limited|Process for Preparing Levetiracetam and Racemization of - and -2-Amino Butynamide and the Corresponding Acid Derivatives|

---

JP2008542323A|2005-06-01|2008-11-27|ユセベファルマソシエテアノニム|2-Oxo-1-pyrrolidine derivatives, process for producing the same and use thereof|

---

PE20070216A1|2005-07-26|2007-03-27|Ucb Sa|NEW PHARMACEUTICAL COMPOSITIONS INCLUDING LEVETIRACETAM AND PROCESS FOR ITS PREPARATION|

---

US8338621B2|2005-12-21|2012-12-25|Ucb S.A.|Process for the preparation of 2-oxo-1-pyrrolidine derivatives|

---

PT1810676E|2006-01-24|2009-01-02|Teva Pharma|Levetiracetam formulations and methods for their manufacture|

---

US20080014264A1|2006-07-13|2008-01-17|Ucb, S.A.|Novel pharmaceutical compositions comprising levetiracetam|

---

EP2049476A1|2006-07-25|2009-04-22|ZaCh System S.p.A.|Process for the preparation of levetiracetam|

---

WO2008021666A2|2006-08-18|2008-02-21|Morton Grove Pharmaceuticals, Inc.|Stable liquid levetiracetam compositions and methods|

---

CN101130504B|2006-08-25|2010-07-28|苏州雅本化学股份有限公司|Synthesis, split and racemization method for preparing chirality medicament levetiracetam midbody --2-amido butyramide hydrochlorate|

---

EP1932922A1|2006-12-13|2008-06-18|Desitin Arzneimittel GmbH|In situ hybridisation detection of DNA squences|

---

WO2008077035A2|2006-12-18|2008-06-26|Dr. Reddy's Laboratories Ltd.|Processes for the preparation of levetiracetam|

---

CN101333180B|2007-06-29|2011-05-18|浙江华海药业股份有限公司|Method for preparing levetiracetam intermediate|

---

US20090082422A1|2007-09-26|2009-03-26|Protia, Llc|Deuterium-enriched levetiracetam|

---

WO2009050735A1|2007-10-15|2009-04-23|Lupin Limited|A novel polymorph of levetiracetam and a process for its preparation|

---

US20090263481A1|2008-04-17|2009-10-22|Atul Vishvanath Patil|Levetiracetam formulations|

---

US20100003322A1|2008-07-03|2010-01-07|Lai Felix S|Enteric coated hydrophobic matrix formulation|

---

EP2147911A1|2008-07-24|2010-01-27|ZaCh System S.p.A.|Process for the preparation of levetiracetam|

---

US20100190752A1|2008-09-05|2010-07-29|Gruenenthal Gmbh|Pharmaceutical Combination|

---

EP3260118B1|2008-10-16|2021-03-24|The Johns Hopkins University|Methods and compositions for improving cognitive function|

---

EP2179725A1|2008-10-23|2010-04-28|LEK Pharmaceuticals D.D.|Pharmaceutical composition comprising levetiracetam|

---

CA2741660A1|2008-11-07|2010-05-14|Novabay Pharmaceuticals, Inc.|Antimicrobial oxazolidinone, hydantoin and imidazolidinone compositions|

---

US20100159009A1|2008-12-24|2010-06-24|Zhongshui Yu|Controlled-release formulations|

---

US20100172979A1|2008-12-24|2010-07-08|Zhongshui Yu|Controlled-release formulations|

---

US8785661B2|2009-05-13|2014-07-22|Nektar Therapeutics|Oligome-containing pyrrolidine compounds|

---

CN101885696A|2009-05-14|2010-11-17|上海华理生物医药有限公司|Method for synthesizing high-purity levetiracetam|

---

US20120171125A1|2009-08-07|2012-07-05|Ucb Pharma, S.A.|Methods for Enhancing the Cognitive Function|

---

EP2298290A1|2009-09-16|2011-03-23|LEK Pharmaceuticals d.d.|Controlled release composition comprising levetiracetam|

---

US7939676B2|2009-09-17|2011-05-10|Zach System S.P.A.|Process for the preparation of levetiracetam|

---

EA201200616A1|2009-10-23|2012-12-28|Юсб Фарма, С.А.|DERIVATIVES 2-OXO-1-PIRROLIDININILIMIDAZOTHIAADIA ASOL|

---

WO2011100373A1|2010-02-09|2011-08-18|The Johns Hopkins University|Methods and compositions for improving cognitive function|

---

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---

WO2011136751A2|2010-04-26|2011-11-03|Mahmut Bilgic|Water soluble pharmaceutical composition|

---

US9333175B2|2010-06-16|2016-05-10|Mylan Inc.|Controlled release levetiracetam formulations and methods for producing the same|

---

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---

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---

EP2524910A1|2011-05-17|2012-11-21|DSM IP Assets B.V.|Process for the resolution of aminobutyramide|

---

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---

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---

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---

CN102675181B|2012-06-07|2013-11-20|北京师宏药物研制中心|Preparation method of levetiracetam|

---

CN102702063B|2012-06-15|2013-09-04|孙威|Method for preparing levetiracetam|

---

WO2014012563A1|2012-07-20|2014-01-23|Ucb Pharma, S.A.|Compounds for enhancing the cognitive function|

---

US20140206667A1|2012-11-14|2014-07-24|Michela Gallagher|Methods and compositions for treating schizophrenia|

---

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---

CA2904767A1|2013-03-15|2014-09-18|Agenebio, Inc.|Methods and compositions for improving cognitive function|

---

JP6170234B2|2013-03-15|2017-07-26|アプレシア・ファーマスーティカルズ・カンパニー|A rapidly dispersing dosage form containing levetiracetam|

---

WO2014144663A1|2013-03-15|2014-09-18|The Johns Hopkins University|Methods and compositions for improving cognitive function|

---

US9339489B2|2013-03-15|2016-05-17|Aprecia Pharmaceuticals Company|Rapid disperse dosage form containing levetiracetam|

---

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---

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---

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---

CN104860863B|2015-04-10|2017-06-20|惠州信立泰药业有限公司|Levetiracetam and the pharmaceutical composition containing it|

---

US10159648B2|2015-05-22|2018-12-25|Agenebio, Inc.|Extended release pharmaceutical compositions of levetiracetam|

---

AU2016381366A1|2015-12-30|2018-06-28|Adamas Pharmaceuticals, Inc.|Methods and compositions for the treatment of seizure-related disorders|

---

CN106432032B|2016-09-14|2019-07-12|苏州天马药业有限公司|A kind of preparation method of Levetiracetam|

---

CN106591179B|2016-12-05|2018-07-03|长兴制药股份有限公司|Methyl packing bacterium and its prepare the application on -α-ethyl -2- oxygen -1- pyrrolidine acetic acid salt in selective fractionation|

---

KR20210065206A|2016-12-16|2021-06-03|이도르시아 파마슈티컬스 리미티드|Pharmaceutical combination comprising a t-type calcium channel blocker|

---

CN108503610B|2017-02-24|2019-09-13|北京艾百诺医药股份有限公司|A kind of preparation method of optically pure-4- n-propyl-dihydrofuran -2-one|

---

CN107337628B|2017-08-10|2022-02-08|浙江华海药业股份有限公司|Method for preparing levetiracetam|

---

TW202023547A|2018-09-21|2020-07-01|南韓愛思開生物製藥股份有限公司|Compound having oxadiazole and pharmaceutical composition containing the same|

---

CN110003074A|2019-04-23|2019-07-12|浙江华海药业股份有限公司|A kind of preparation method of levetiracetam intermediate|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB848412357A|GB8412357D0|1984-05-15|1984-05-15|Pharmaceutical composition|

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